First-pass metabolism of inspired ethyl acetate in the upper respiratory tracts of the F344 rat and Syrian hamster.
Nasal tissues contain large amounts of carboxylesterase but its precise role in metabolism of inspired ester vapors is not known. The current study was aimed at quantitating the extent of metabolism of inspired ethyl acetate in the upper respiratory tract (URT) of the F344 rat and Syrian hamster. Ethyl acetate deposition was measured in the surgically isolated URT of these species under constant velocity unidirectional flow conditions. The degree of metabolism was estimated by mathematic modeling based on a simple venous-equilibration approach and by direct comparison of deposition efficiencies in naive and carboxylesterase-inhibited animals. Ethyl acetate deposition efficiencies averaged between 10 and 35% in the rat URT and 36 and 72% in the hamster. Carboxylesterase inhibition decreased deposition in both species. Both the modeling efforts and the direct comparisons between naive and inhibited animals indicated that significant amounts of the deposited ethyl acetate were metabolized in the URT of both species with the extent of metabolism being more pronounced in the hamster. Specifically, 40-65% of the deposited ethyl acetate was metabolized in the URT of the rat compared to 63-90% in the hamster. This first-pass metabolism (i) increased URT deposition efficiencies; (ii) led to production of high metabolite levels in URT tissues; and (iii) decreased the amount of parent ethyl acetate available for absorption into the bloodstream in the URT.
Morris
J B
JB
Toxicology Program, School of Pharmacy, University of Connecticut, Storrs 06268.
D000085:Acetates / Q000008:administration & dosage / Q000378:metabolism*; D000096:Acetone / Q000378:metabolism; D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006224:Cricetinae; D006868:Hydrolysis; D007700:Kinetics; D008297:Male; D008647:Mesocricetus; D009296:Nasal Cavity / Q000201:enzymology*; D009596:Nitrophenols / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D014317:Tritolyl Phosphates / Q000494:pharmacology
D000085:Acetates; D009596:Nitrophenols; D014317:Tritolyl Phosphates; D000096:Acetone; C002887:bis(4-nitrophenyl)phosphate; C007650:ethyl acetate; D002265:Carboxylic Ester Hydrolases; C025541:tri-o-cresyl phosphate